Prodrugs are typically pharmacologically inactive derivatives of drugs that are designed to maximize the amount of active drug that reaches the locus of drug action. The physicochemical, biopharmaceutical and/or pharmacokinetic properties of the parent drug may be altered by conversion to a prodrug. Prodrugs are converted into active drugs within the body through enzymatic or non-enzymatic reactions. Typically, in a prodrug, a polar functional group (e.g., a hydroxyl group, an amino group, a carboxylic acid, etc.) of a drug is masked by a promoiety, which is labile under physiological conditions. Ideally, cleavage of the promoiety occurs rapidly and quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety or promoieties).
The acyloxyalkyl group may be used to mask many functional groups (e.g., amines, carboxylic acids, and alcohols) and hence, is one the most useful promoieties for improving the bioavailability of poorly absorbed drugs. The substituents on the acyloxyalkyl promoiety of an acyloxyalkyl prodrug may control the rate of regeneration of the parent drug and may also modulate the physicochemical properties of the prodrug (see, e.g., Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S. Pat. No. 5,733,907; Alexander et al., U.S. Pat. No. 4,426,391).
Existing methods for synthesis of acyloxyalkyl prodrugs require multiple steps that utilize unstable intermediates and/or toxic reagents and are inconvenient to perform on a manufacturing scale (Alexander, U.S. Pat. No. 4,760,057; Lund, U.S. Pat. No. 5,401,868; Alexander, U.S. Pat. No. 4,916,230; Saari et al., European Patent No. 0416689B1). Moreover, most existing methods of acyloxyalkyl prodrug synthesis lack stereoselectivity, thus providing a mixture of stereoisomeric prodrugs from prochiral starting materials. Frequently, the biological, pharmacokinetic, and/or the physicochemical properties of two individual stereoisomers of a drug or prodrug differ from one another, or from a racemic mixture (Oszczapowicz, et al., Drug Research 1995, 52, 471-476; Klecker et al., J. Cardiovasc. Pharmacol. 1997, 30, 69-74). One method that selectively provides one stereoisomer of an acyloxyalkyl compound is oxidation of optically active O-acyl-α-hydroxyketones to provide chiral acyloxyalkyl esters (Cooper et al., Synlett. 1990, 533-535; Ziegler et al., Tetrahedron Lett. 1993, 34, 7669-7672; List et al., J. Am. Chem. Soc. 2002, 124, 827-833; Gallop et al., International Publication No. WO 2003/077902). The standard oxidation reaction conditions involve the use of peroxycarboxylic acids as oxidants. Peroxysulfonic acids and peroxysulfuric acid (Caro's reagent) are also suitable oxidants (e.g., Pfirmann, U.S. Pat. No. 5,481,032; Odinokov et al., Izvest. Akad. Nauk, Ser. Khim. 1993, 7, 1301-1302). Also, various acids and bases are typically used in these oxidations to improve the reaction yields. However, acyloxyalkyl prodrugs can readily undergo hydrolytic cleavage to release the parent drug compounds in the presence of either aqueous acid or base. Further, the common commercially available peroxycarboxylic acids (e.g., m-chloroperbenzoic acid) contain significant amounts of the corresponding carboxylic acids (i.e., m-chlorobenzoic acid) and water. Accordingly, standard oxidants and reaction protocols are not optimal for the oxidation of acylalkyl derivatives to the corresponding acyloxyalkyl derivatives, under conditions that maximize the yields of the desired acyloxyalkyl products. Thus, there is a need for a general method for synthesis of acyloxyalkyl prodrugs which is both stereoselective and suitable for large-scale synthesis under mild reaction conditions.